Search

Hyperacusis, a debilitating loudness intolerance disorder, has been linked to chronic stress and adrenal insufficiency. To investigate the role of chronic stress, rats were chronically treated with corticosterone (CORT) stress hormone. Chronic CORT produced behavioral evidence of loudness hyperacusis, sound avoidance hyperacusis, and abnormal temporal integration of loudness. CORT treatment did not disrupt cochlear or brainstem function as reflected by normal distortion product otoacoustic emissions, compound action potentials, acoustic startle reflexex, and auditory brainstem responses. In contrast, the evoked response from the auditory cortex was enhanced up to three fold after CORT treatment. This hyperactivity was associated with a significant increase in glucocorticoid receptors in auditory cortex layers II/III and VI. Basal serum CORT levels remained normal after chronic CORT stress whereas reactive serum CORT levels evoked by acute restraint stress were blunted (reduced) after chronic CORT stress; similar changes were observed after chronic, intense noise stress. Taken together, our results show for the first time that chronic stress can induce hyperacusis and sound avoidance. A model is proposed in which chronic stress creates a subclinical state of adrenal insufficiency that establishes the necessary conditions for inducing hyperacusis., Competing Interests: Declaration of Competing Interest The authors declare no conflicts of interest in the publication of this manuscript., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Hyperacusis is a debilitating loudness intolerance disorder that can evoke annoyance, fear and aural facial pain. Although the auditory system seems to be the "central" player, hyperacusis is linked to more than twenty non-auditory medical disorders such as Williams syndrome, autism spectrum disorder, fibromyalgia, migraine, head trauma, lupus and acoustic shock syndrome. Neural models suggest that some forms of hyperacusis may result from enhanced central gain, a process by which neural signals from a damaged cochlea are progressively amplified as activity ascends rostrally through the classical auditory pathway as well as other non-auditory regions of the brain involved in emotions, memory and stress. Imaging studies have begun to reveal the extended neural networks and patterns of functional connectivity in the brain that enrich sounds with negative attributes that can make listening unbearable and even painful. The development of animal models of hyperacusis have enabled researcher to begin to critically evaluate the biological bases of hyperacusis, identify therapies to ameliorate the symptoms and gain a better understanding of the neural mechanisms involved in loudness coding in normal and hearing impaired subjects., Competing Interests: Competing Interest The authors declare they have no conflict or competing interests in the publication of this manuscript., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background: While ear stimulation produces a robust response in the contralateral auditory cortex (AC), it produces only a weak response in the ipsilateral AC, known as interhemispheric asymmetry. Unilateral deafness can lead to AC plastic changes, resulting in reduced interhemispheric asymmetry and auditory perceptual consequences. However, the unilateral hearing loss-associated plastic changes are far from fully understood. The purpose of this study was to investigate AC responses to the ipsilateral unimpaired ear after noise injury to the contralateral ear in juvenile rats., Methods: Rats (50 days) were monaurally exposed to an intense noise (10.0-12.5 kHz, 126 dB SPL) for 2 hours. The unexposed ear-induced ipsilateral AC responses were recorded 2 days and 4 months after exposure and compared between groups., Results: The noise exposure resulted in complete hearing loss in the exposed ear, but normal function in the other. Two days after exposure, the ipsilateral AC response induced by the intact ear was significantly enhanced and the threshold decreased (the early-onset effect). Four months after noise exposure, in addition to the increased response amplitude, the "slow-increasing" firing pattern of the neurons in the ipsilateral AC turned into the contralateral-AC-response-like "sharp-increasing" pattern (the late-onset effect) with shortened response latency., Discussion: The early-onset effect can result from release of inhibition due to decreased contralateral input, while the late-onset effect may imply the formation of direct connections in the ipsilateral auditory pathway. The enhanced AC response may help maintain loudness perception and monaural sound localization after unilateral deafness., Competing Interests: Declaration of Competing Interest We declare that the authors have no conflict of interest related to this manuscript., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background: Levetiracetam (LEV, 5-100 mg/kg) has been shown to prevent audiogenic seizures in a dose-dependent manner. This chemical is known to bind to synaptic vesicle protein 2A and inhibit l-type calcium channels, affecting neurotransmitter release. We hypothesize that the drug prevents audiogenic seizures partially by affecting cochlear neural response., Methods: To test this hypothesis, rats were given 1000, 500, 50, or 0 mg/kg (saline control) LEV-injection. Distortion product otoacoustic emissions (DPOAE), reflecting outer hair cell (OHC) function, and cochlear compound action potentials (CAP), reflecting cochlear neural output, were recorded and compared pre- and post-LEV., Results: 1000 mg/kg LEV-injection did not significantly affect DPOAE. The high dose LEV-injection, however, significantly reduced CAP amplitude resulting threshold shift (TS), prolonged CAP latency, and enhanced CAP forward masking. CAP latency and forward masking were significantly affected at the 500 mg/kg dose, but CAP-TS remained unchanged after LEV-injection. Interestingly, CAP latency wassignificantly prolonged, at least at the low stimulation levels, although the amplitude of CAP remained constant after a clinical dose of LEV-injection (50 mg/kg)., Discussion: Since the clinical dose of LEV-injection does not reduce CAP amplitude, the reduction of cochlear neural output is unlikely to be the underlying mechanism of LEV in the treatment of audiogenic seizure. The delayed cochlear neural response may be partially related to the prevention of audiogenic seizure. However, neuropharmacological changes in the central nervous system must play a major role in the treatment of audiogenic seizure, as it does in the treatment of focal epilepsy., Competing Interests: Declaration of Competing Interest The authors declare no competing financial interests or conflicts of interest., (Copyright © 2021. Published by Elsevier B.V.)

Niemann-Pick C1 (NPC1) is a fatal neurodegenerative disease caused by aberrant cholesterol metabolism. The progression of the disease can be slowed by removing excess cholesterol with high-doses of 2-hyroxypropyl-beta-cyclodextrin (HPβCD). Unfortunately, HPβCD causes hearing loss; the initial first phase involves a rapid destruction of outer hair cells (OHCs) while the second phase, occurring 4-6 weeks later, involves the destruction of inner hair cells (IHCs), pillar cells, collapse of the organ of Corti and spiral ganglion neuron degeneration. To determine whether the first and/or second phase of HPβCD-induced cochlear damage is linked, in part, to excess oxidative stress or neuroinflammation, rats were treated with a single-dose of 3000 mg/kg HPβCD alone or together with one of two combination therapies. Each combination therapy was administered from 2-days before to 6-weeks after the HPβCD treatment. Combination 1 consisted of minocycline, an antibiotic that suppresses neuroinflammation, and HK-2, a multifunctional redox modulator that suppresses oxidative stress. Combination 2 was comprised of minocycline plus N-acetyl cysteine (NAC), which upregulates glutathione, a potent antioxidant. To determine if either combination therapy could prevent HPβCD-induced hearing impairment and cochlear damage, distortion product otoacoustic emissions (DPOAE) were measured to assess OHC function and the cochlear compound action potential (CAP) was measured to assess the function of IHCs and auditory nerve fibers. Cochleograms were prepared to quantify the amount of OHC, IHC and pillar cell (PC) loss. HPβCD significantly reduced DPOAE and CAP amplitudes and caused significant OHC, IHC and OPC losses with losses greater in the high-frequency base of the cochlea than the apex. Neither minocycline + HK-2 (MIN+ HK-2) nor minocycline + NAC (MIN+NAC) prevented the loss of DPOAEs, CAPs, OHCs, IHCs or IPCs caused by HPβCD. These results suggest that oxidative stress and neuroinflammation are unlikely to play major roles in mediating the first or second phase of HPβCD-induced cochlear damage. Thus, HPβCD-induced ototoxicity must be mediated by some other unknown cell-death pathway possibly involving loss of trophic support from damaged support cells or disrupted cholesterol metabolism., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: High doses of salicylate are known to reduce cochlear response amplitude and raise threshold. However, its effect on the cochlear forward masking, reflecting temporal resolution, is still unclear., Methods: The neural forward masking of cochlea was evaluated using double-tone stimulation. The first tone burst (5ms) was named the "masker" and the second tone burst (5 ms) was named the "probe". The frequency and intensity of the masker and probe were equal, and the masker-probe interval varied from 2 to 32 ms. The reduction (%) of the probe-evoked cochlear compound action potential caused by the addition of the masker tone was used to represent cochlear forward masking. The data obtained before and 2 h following the injection of sodium salicylate (250 mg/kg) were compared., Results: The neural forward masking of cochlea in the normal rats increased as the masker-probe interval decreased. At 16 kHz, for example, it increased from ~5% to 32ms masker-probe interval to ~85% at 2ms masker-probe interval. Two hours post salicylate injection, the neural forward masking was significantly enhanced except at 32 ms masker-probe interval. Interestingly, this enhancement was only observed in the limited frequency range of 16-30 kHz., Discussion: The enhancement of forward masking of cochlea following salicylate administration may reflect defective neurotransmitter release. This frequency-dependent injury in the cochlea may lead to the development of central plasticity observed after salicylate administration, likely through the increase in central gain, leading to perceptual consequences., (Copyright © 2021. Published by Elsevier B.V.)

Long-term exposure to moderate intensity noise that does not cause measureable hearing loss can cause striking changes in sound-evoked neural activity in auditory cortex.  It is unclear if these changes originate in the cortex or result from functional deficits in the neural output of the cochlea.  To explore this issue, rats were exposed for 6-weeks to 18-24 kHz noise at 45, 65 or 85 dB SPL and then compared the noise-induced changes in the cochlear compound action potential (CAP) with the neurophysiological alterations in the anterior auditory field (AAF) of auditory cortex. The 45-dB exposure, which had no effect on the cochlear CAP also had no effect on the AAF. In contrast, the 85-dB exposure greatly reduced CAP amplitudes at high frequencies, but had little or no effect on low frequencies. Despite the large reduction in high-frequency CAP neural responses, high frequency AAF neural responses (spike rate and local field potential amplitude) remained largely within normal limits, evidence of central gain compensation. AAF responses were also enhanced at the low frequencies even though CAP responses were normal; this AAF hyperactivity only occurred at low-moderate intensities (level-dependent enhanced central gain). The 65-dB exposure also caused a moderate reduction in high-frequency CAP amplitudes. Notwithstanding this cochlear loss, AAF responses were boosted into the normal range, evidence of homeostatic gain compensation. Our results suggest that the noise-induced neuroplastic changes in the auditory cortex from so-called "non-traumatic" exposures are triggered from functional deficits in the neural output of the cochlea., Competing Interests: Declaration of Competing Interest The authors declare no competing financial interests or conflicts of interest., (Copyright © 2021. Published by Elsevier B.V.)

The effect of intense noise on cochlear sensitivity has been extensively studied, but its influence on the temporal characteristics of the cochlear response is still unclear. This study investigated the effects of noise exposure on the latency of cochlear response and cochlear forward masking. Rats were exposed to an octave band noise (8-16 kHz) at 90 dB SPL for 5 days. Cochlear compound action potentials (CAPs) induced by single- and double-tone stimuli and distortion product otoacoustic emissions (DPOAE) were recorded 1 day or 2 months after the noise exposure. The latency of the CAP and its forward masking were compared between the noise-exposed rats and normal control rats. The noise exposure significantly reduced DPOAE and elevated CAP threshold in the noise band region, but not in the other areas. Even in the noise band area, the noise did not reduce CAP-amplitude at the high stimulation level (80 dB SPL). Correspondingly, about one-third of the outer hair cells (OHC) in the noise band area disappeared, while the inner hair cells (IHC) did not. However, the noise exposure in the frequency range of 4-24 kHz significantly prolonged CAP latency and increased its variability, while the CAP forward masking effect was significantly enhanced in the frequency range of 16-30 kHz. The frequency-dependent changes in CAP latency and forward masking after noise exposure may reflect different types of synaptic subinjury in the cochlea, which may lead to psychophysical consequences of sound localization and speech recognition., Competing Interests: Declaration of Competing Interest The authors declare no competing financial interests or conflicts of interest., (Copyright © 2021. Published by Elsevier B.V.)

Acoustic information transduced by cochlear hair cells is continuously relayed from the auditory pathway to other sensory, motor, emotional and cognitive centers in the central nervous system. Human epidemiological studies have suggested that hearing loss is a risk factor for dementia and cognitive decline, but the mechanisms contributing to these memory and cognitive impairments are poorly understood. To explore these issues in a controlled experimental setting, we exposed adult rats to a series of intense blast wave exposures that significantly reduced the neural output of the cochlea. Several weeks later, we used the Morris Water Maze test, a hippocampal-dependent memory task, to assess the ability of Blast Wave and Control rats to learn a spatial navigation task (memory acquisition) and to remember what they had learned (spatial memory retention) several weeks earlier. The elevated plus maze and open field arena were used to test for anxiety-like behaviors. Afterwards, hippocampal cell proliferation and neurogenesis were evaluated using bromodeoxyuridine (BrdU), doublecortin (DCX), and Neuronal Nuclei (NeuN) immunolabeling. The Blast Wave and Control rats learned the spatial navigation task equally well and showed no differences on tests of anxiety. However, the Blast Wave rats performed significantly worse on the spatial memory retention task, i.e., remembering where they had been two weeks earlier. Deficits on the spatial memory retention task were associated with significant decreases in hippocampal cell proliferation and neurogenesis. Our blast wave results are consistent with other experimental manipulations that link spatial memory retention deficits (long term memory) with decreased cell proliferation and neurogenesis in the hippocampus. These results add to the growing body of knowledge linking blast-induced cochlear hearing loss with the cognitive deficits often seen in combat personnel and provide mechanistic insights into these extra auditory disorders that could lead to therapeutic interventions., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Prolonged exposure to low-level noise has often been used scientifically as well as clinically to induce neuroplastic changes within the central auditory pathway in order to reduce central gain, suppress tinnitus and hyperacusis, and modulate different features of central auditory processing. A fundamental assumption underling these studies is that the noise exposure levels are so low that they have no effect on the neural output of the cochlea. Therefore, functional changes occurring in the central auditory pathway must be the results of central rather than peripheral changes. In an attempt to identify long-term noise exposures that did not cause peripheral changes, we measured the compound action potential (CAP) input/output functions from control rats and rats exposed for 6-weeks to 18-24 kHz noise presented at 25, 45, 55, 65, 75 or 85 dB SPL. Exposures >65 dB SPL significantly increased CAP thresholds; the critical intensity (Ct) below which no threshold shift occurred was estimated to be 55 dB SPL. Exposures >55 dB SPL significantly reduced suprathreshold CAP amplitudes; the critical intensity (Ca) below which no amplitude change was predicted to occur was a remarkably low level of 19 dB SPL. These results demonstrate that even extremely low-intensity long duration exposures can disrupt the neural output of the cochlea; these peripheral modifications are likely to contribute to the extensive compensatory changes observed at multiple levels of the central auditory pathway, neural network changes aimed at re-establishing homeostasis., Competing Interests: Declaration of competing interest The authors declare no competing financial interests or conflicts of interest., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Hyperacusis is a debilitating hearing condition in which normal everyday sounds are perceived as exceedingly loud, annoying, aversive or even painful. The prevalence of hyperacusis approaches 10%, making it an important, but understudied medical condition. To noninvasively identify the neural correlates of hyperacusis in an animal model, we used sound-evoked functional magnetic resonance imaging (fMRI) to locate regions of abnormal activity in the central nervous system of rats with behavioral evidence of hyperacusis induced with an ototoxic drug (sodium salicylate, 250 mg/kg, i.p.). Reaction time-intensity measures of loudness-growth revealed behavioral evidence of salicylate-induced hyperacusis at high intensities. fMRI revealed significantly enhanced sound-evoked responses in the auditory cortex (AC) to 80 dB SPL tone bursts presented at 8 and 16 kHz. Sound-evoked responses in the inferior colliculus (IC) were also enhanced, but to a lesser extent. To confirm the main results, electrophysiological recordings of spike discharges from multi-unit clusters were obtained from the central auditory pathway. Salicylate significantly enhanced tone-evoked spike-discharges from multi-unit clusters in the AC from 4 to 30 kHz at intensities ≥60 dB SPL; less enhancement occurred in the medial geniculate body (MGB), and even less in the IC. Our results demonstrate for the first time that non-invasive sound-evoked fMRI can be used to identify regions of neural hyperactivity throughout the brain in an animal model of hyperacusis., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Oxidative stress is a major contributor to noise-induced hearing loss, the most common cause of hearing loss among military personnel and young adults. HK-2 is a potent, orally-active, multifunctional, redox-modulating drug that has been shown to protect against a wide range of neurological disorders with no observed side effects. HK-2 protected cochlear HEI-OC1 cells against various forms of experimentally-induced oxidative stressors similar to those observed during and after intense noise exposure. The mechanisms by which HK-2 protects cells is twofold, first by its ability to reduce oxidative stress generated by free radicals, and second, by its ability to complex biologically active transition metals such as Fe +2 , thus reducing their availability to participate in the Fenton reaction where highly toxic hydroxyl radicals are generated. For the rat in vivo studies, HK-2 provided significant protection against noise-induced hearing loss and hair cell loss. Noise-induced hearing loss was induced by an 8-16 kHz octave band noises presented for 8 h/d for 21 days at an intensity of 95 dB SPL. In the Prevention study, HK-2 was administered orally beginning 5 days before the start of the noise and ending 10 days after the noise. Treatment with HK-2 dose-dependently reduced the amount of noise-induced hearing impairment, reflected in the cochlear compound action potential, and noise-induced hair cell loss. In a subsequent Rescue experiment in which HK-2 was administered for 10 days starting after the noise was turned off, HK-2 also significantly reduced the amount of hearing impairment, but the effect size was substantially less than in the Prevention studies. HK-2 alone did not adversely affect HEI-OC1 cell viability, nor did it cause any adverse changes in rat body weight, behavior, cochlear function or hair cell integrity. Thus, HK-2 is a novel, safe, orally-deliverable and highly effective otoprotective compound with considerable potential for preventing hearing loss from noise and other hearing disorders linked to excessive oxidative stress., Competing Interests: Declaration of competing interest Peter Kador is the President of Therapeutic Vision and hold the patent on HK-2. Dr. Salvi was the PI on a subaward on an NIH grant (1R43DC016766-01) to Therapeutic Vision to test the efficacy of HK-2., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Chronic tinnitus and hyperacusis often develop with age-related hearing loss presumably due to aberrant neural activity in the central auditory system (CAS) induced by cochlear pathologies. However, the full spectrum of physiological changes that occur in the CAS as a result age-related hearing loss are still poorly understood. To address this issue, neurophysiological measures were obtained from the cochlea and the inferior colliculus (IC) of 2, 6 and 12 month old C57BL/6J mice, a mouse model for early age-related hearing loss. Thresholds of the compound action potentials (CAP) in 6 and 12 month old mice were significantly higher than in 2 month old mice. The sound driven and spontaneous firing rates of IC neurons, recorded with 16 channel electrodes, revealed mean IC thresholds of 22.8 ± 6.5 dB (n = 167) at 2 months, 37.9 ± 6.2 dB (n = 132) at 6 months and 47.1 ± 15.3 dB (n = 151) at 12 months of age consistent with the rise in CAP thresholds. The characteristic frequencies (CF) of IC neurons ranged from 3 to 32 kHz in 2 month old mice; the upper CF ranged decreased to 26 kHz and 16 kHz in 6 and 12 month old mice respectively. The percentage of IC neurons with CFs between 8 and 12 kHz increased from 36.5% in 2 month old mice, to 48.8% and 76.2% in 6 and 12 month old mice, respectively, suggesting a downshift of IC CFs due to the high-frequency hearing loss. The average spontaneous firing rate (SFRs) of all recorded neurons in 2 month old mice was 3.2 ± 2.5 Hz (n = 167). For 6 and 12 month old mice, the SFRs of low CF neurons (<8 kHz) was maintained at 3-6 spikes/s; whereas SFRs of IC neurons with CFs > 8 kHz increased to 13.0 ± 15.4 (n = 68) Hz at 6 months of age and then declined to 4.8 ± 7.4 (n = 110) spikes/s at 12 months of age. In addition, sound-evoked activity at suprathreshold levels at 6 months of age was much higher than at 2 and 12 months of age. To evaluate the behavioral consequences of sound evoked hyperactivity in the IC, the amplitude of the acoustic startle reflex was measured at 4, 8 and 16 kHz using narrow band noise bursts. Acoustic startle reflex amplitudes in 6 and 12 month old mice (n = 4) were significantly larger than 2 month old mice (n = 4) at 4 and 8 kHz, but not 16 kHz. The enhanced reflex amplitudes suggest that high-intensity, low-frequency sounds are perceived as louder than normal in 6 and 12 month old mice compared to 2 month olds. The increased spontaneous activity, particularly at 6 months, may be related to tinnitus whereas the increase in sound-evoked activity and startle reflex amplitudes may be related to hyperacusis., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Tinnitus and hyperacusis are common and potentially serious hearing disorders associated with noise-, age- or drug-induced hearing loss. Accumulating evidence suggests that tinnitus and hyperacusis are linked to excessive neural activity in a distributed brain network that not only includes the central auditory pathway, but also brain regions involved in arousal, emotion, stress and motor control. Here we examine electrophysiological changes in two novel non-auditory areas implicated in tinnitus and hyperacusis: the caudal pontine reticular nucleus (PnC), involved in arousal, and the paraflocculus lobe of the cerebellum (PFL), implicated in head-eye coordination and gating tinnitus and we measure the changes in corticosterone stress hormone levels. Using the salicylate-induced model of tinnitus and hyperacusis, we found that long-latency (>10 ms) sound-evoked response components in both the brain regions were significantly enhanced after salicylate administration, while the short-latency responses were reduced, likely reflecting cochlear hearing loss. These results are consistent with the central gain model of tinnitus and hyperacusis, which proposes that these disorders arise from the amplification of neural activity in central auditory pathway plus other regions linked to arousal, emotion, tinnitus gating and motor control. Finally, we demonstrate that salicylate results in an increase in corticosterone level in a dose-dependent manner consistent with the notion that stress may interact with hearing loss in tinnitus and hyperacusis development. This increased stress response has the potential to have wide-ranging effects on the central nervous system and may therefore contribute to brain-wide changes in neural activity., (Copyright © 2017 Elsevier B.V. All rights reserved.)

High dose of salicylate, the active ingredient in aspirin, has long been known to induce transient hearing loss, tinnitus and hyperacusis making it a powerful experimental tool. These salicylate-induced perceptual disturbances are associated with a massive reduction in the neural output of the cochlea. Paradoxically, the diminished neural output of the cochlea is accompanied by a dramatic increase in sound-evoked activity in the auditory cortex (AC) and several other parts of the central nervous system. Exactly where the increase in neural activity begins and builds up along the central auditory pathway are not fully understood. To address this issue, we measured sound-evoked neural activity in the cochlea, cochlear nucleus (CN), inferior colliculus (IC), and AC before and after administering a high dose of sodium salicylate (SS, 300 mg/kg). The SS-treatment abolished low-level sound-evoked responses along the auditory pathway resulting in a 20-30 dB threshold shift. While the neural output of the cochlea was substantially reduced at high intensities, the neural responses in the CN were only slightly reduced; those in the IC were nearly normal or slightly enhanced while those in the AC considerably enhanced, indicative of a progress increase in central gain. The SS-induced increase in central response in the IC and AC was frequency-dependent with the greatest increase occurring in the mid-frequency range the putative pitch of SS-induced tinnitus. This frequency-dependent hyperactivity appeared to result from shifts in the frequency receptive fields (FRF) such that the response areas of many FRF shifted/expanded toward the mid-frequencies. Our results suggest that the SS-induced threshold shift originates in the cochlea. In contrast, enhanced central gain is not localized to one region, but progressively builds up at successively higher stage of the auditory pathway either through a loss of inhibition and/or increased excitation., (Copyright © 2016. Published by Elsevier B.V.)

Sodium Salicylate (SS) reliably induces a sensorineural hearing loss and tinnitus when administered in high doses. Recent animal modeled studies indicate that potassium channel openers such as Maxipost and Retigabine (RTG) can block SS- or noise-induced tinnitus respectively; however, the origins and mechanisms are poorly understood. Since SS blocks the same potassium channels that Maxipost and RTG open, we postulated that these drugs might influence peripheral auditory function. To test this hypothesis Maxipost or RTG were administered alone or in combination with SS in rats. When administered alone, Maxipost and RTG had no effect on distortion product otoacoustic emissions (DPOAE) or compound action potentials (CAPs). However when Maxipost or RTG were administered with SS, Maxipost prevented the SS-reduced CAP amplitudes at high frequencies (≥20 kHz) and RTG prevented SS-reduced CAP amplitudes at low frequencies (≤8 kHz). These results suggest that Maxipost and RTG can protect against peripheral damage and therefore reduce the incidence of tinnitus., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Noise-induced hearing loss (NIHL) initially increases with exposure duration, but eventually reaches an asymptotic threshold shift (ATS) once the exposure duration exceeds 18-24 h. Equations for predicting the ATS have been developed for several species, but not for rats, even though this species is extensively used in noise exposure research. To fill this void, we exposed rats to narrowband noise (NBN, 16-20 kHz) for 5 weeks starting at 80 dB SPL in the first week and then increasing the level by 6 dB per week to a final level of 104 dB SPL. Auditory brainstem responses (ABR) were recorded before, during, and following the exposure to determine the amount of hearing loss. The noise induced threshold shift to continuous long-term exposure, defined as compound threshold shift (CTS), within and above 16-20 kHz increased with noise level at the rate of 1.82 dB threshold shift per dB of noise level (NL) above a critical level (C) of 77.2 dB SPL i.e. CTS = 1.82(NL-77.2). The normalized amplitude of the largest ABR peak measured at 100 dB SPL decreased at the rate of 3.1% per dB of NL above the critical level of 76.9 dB SPL, i.e., %ABR Reduction = 3.1%(NL-76.9). ABR thresholds measured >30 days post-exposure only partially recovered resulting in a permanent threshold shift of 30-40 dB along with severe hair cell loss in the basal, high-frequency region of the cochlea. In the rat, CTS increases with noise level with a slope similar to humans and chinchillas. The critical level (C) in the rat is similar to that of humans, but higher than that of chinchillas., (Copyright © 2014 Elsevier B.V. All rights reserved.)

High doses of sodium salicylate (SS) have long been known to induce temporary hearing loss and tinnitus, effects attributed to cochlear dysfunction. However, our recent publications reviewed here show that SS can induce profound, permanent, and unexpected changes in the cochlea and central nervous system. Prolonged treatment with SS permanently decreased the cochlear compound action potential (CAP) amplitude in vivo. In vitro, high dose SS resulted in a permanent loss of spiral ganglion neurons and nerve fibers, but did not damage hair cells. Acute treatment with high-dose SS produced a frequency-dependent decrease in the amplitude of distortion product otoacoustic emissions and CAP. Losses were greatest at low and high frequencies, but least at the mid-frequencies (10-20 kHz), the mid-frequency band that corresponds to the tinnitus pitch measured behaviorally. In the auditory cortex, medial geniculate body and amygdala, high-dose SS enhanced sound-evoked neural responses at high stimulus levels, but it suppressed activity at low intensities and elevated response threshold. When SS was applied directly to the auditory cortex or amygdala, it only enhanced sound evoked activity, but did not elevate response threshold. Current source density analysis revealed enhanced current flow into the supragranular layer of auditory cortex following systemic SS treatment. Systemic SS treatment also altered tuning in auditory cortex and amygdala; low frequency and high frequency multiunit clusters up-shifted or down-shifted their characteristic frequency into the 10-20 kHz range thereby altering auditory cortex tonotopy and enhancing neural activity at mid-frequencies corresponding to the tinnitus pitch. These results suggest that SS-induced hyperactivity in auditory cortex originates in the central nervous system, that the amygdala potentiates these effects and that the SS-induced tonotopic shifts in auditory cortex, the putative neural correlate of tinnitus, arises from the interaction between the frequency-dependent losses in the cochlea and hyperactivity in the central nervous system., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Aspirin has been extensively used in clinical settings. Its side effects on auditory function, including hearing loss and tinnitus, are considered as temporary. A recent promising finding is that chronic treatment with high-dose salicylate (the active ingredient of aspirin) for several weeks enhances expression of the outer hair cell (OHC) motor protein (prestin), resulting in strengthened OHC electromotility and enhanced distortion product otoacoustic emissions (DPOAE). To follow up on these observations, we carried out two studies, one planned study of age-related hearing loss restoration and a second unrelated study of salicylate-induced tinnitus. Rats of different strains and ages were injected with salicylate at a dose of 200 mg/kg/day for 5 days per week for 3 weeks or at higher dose levels (250-350 mg/kg/day) for 4 days per week for 2 weeks. Unexpectedly, while an enhanced or sustained DPOAE was seen, permanent reductions in the amplitude of the cochlear compound action potential (CAP) and the auditory brainstem response (ABR) were often observed after the chronic salicylate treatment. The mechanisms underlying these unexpected, permanent salicylate-induced reductions in neural activity are discussed., (2010 Elsevier B.V. All rights reserved.)

Numerous techniques have been tested to attempt to prevent the onset or progression of age-related hearing loss (ARHL): raising the animals in an augmented acoustic environment (used successfully in mouse and rat models), enhancing the antioxidant defenses with exogenous antioxidant treatments (used with mixed results in mouse and rat models), raising the animals with a calorie restricted diet (used successfully in mouse and rat models), restoring lost endocochlear potential voltage with exogenous electrical stimulation (used successfully in the Mongolian gerbil model), and hypothetical enhancement of outer hair cell electromotility with salicylate therapy. Studies of human ARHL have revealed a set of unique hearing loss configurations with unique underlying pathologies. Animal research has developed models for the different forms of age-related peripheral pathology. Using the animal models, different techniques for prevention of ARHL have been developed and tested. The current review discusses ARHL patterns in humans and animal models, followed by discussions of the different prevention techniques., (Copyright 2009 Elsevier B.V. All rights reserved.)

Workers exposed to industrial solvents are also frequently exposed to mechanical noise. In this study, a combination of a continuous noise (100 dB SPL) and an impact noise (110 dB SPL) was used to mimic the noise exposure in the workplace. A noise band of 10-20 kHz was used to induce a cochlear injury in the same cochlear region in the rat as styrene exposure. Styrene levels of 300 and 400mg/kg were applied to induce outer hair cell (OHC) loss limited to the third row of the middle turn, but without significant cochlear functional loss. The combined exposures of the noise and styrene for 3 weeks caused greater threshold shifts than the noise alone, although the styrene alone did not induce significant threshold shift. Correspondingly, the combined exposures induced OHC losses that were greater than the summated OHC losses induced by the noise and styrene exposure alone. Apoptosis in Deiters cells was also examined after a short-term exposure (7 days) to a combined exposure of a high-level styrene (800 mg/kg) and the noise. The styrene-noise synergistic interaction was also observed in the Deiters cells. The synergistic interaction between the noise and styrene suggests that each of the exposures alone (noise or styrene) may cause stress, temporary alteration, or nonlethal injury in cochlear cells and the combined exposure strengthens the stress leading to cell death.

Previous studies reported that exposure to non-traumatic level sounds after traumatic noise exposure reduced the degree of noise-induced hearing loss and hair cell stereocilia damage. The current study investigated the effects of a 3-day post-noise acoustic environment on the degree of noise-induced hearing loss and cochlear damage. Female chinchillas were exposed to traumatic continuous noise (4 kHz octave-band noise) at 107 dB SPL for 1h and then placed in either an augmented acoustic environment (AAE) or deprived acoustic environment (DAE) for 3 days. The AAE group was exposed to a broad-band noise (4-20 kHz) at 80 dB SPL and the DAE animals were fit with conventional earplugs to minimize the level of acoustic stimulation. Auditory brainstem responses (ABRs) were recorded before and 3 days after the traumatic noise exposure. The AAE group showed a significantly lower average threshold shift at the frequencies of 4 and 8 kHz (p<0.01). Correspondingly, significantly fewer missing and dying outer hair cells (OHCs) were observed in the AAE group than in the DAE group. Although the cochlear reduced and oxidized glutathione levels (GSH and GSSG, respectively) were essentially the same in two groups at day 3, significant correlations were found between GSSG levels and mean ABR threshold shift (1-16 kHz) in the AAE group; as well as GSSG and percentage of total OHC loss in the DAE group. The results suggest that post-noise acoustic environment influenced the degree of hearing loss and OHC deterioration after traumatic noise exposure.

As previously reported [Popelar, J., Groh, D., Pelanova, J., Canlon, B., Syka, J., 2006. Age-related changes in cochlear and brainstem auditory functions in Fischer 344 rats. Neurobiol. Aging 27, 490-500; Buckiova, D., Popelar, J., Syka, J., 2007. Aging cochleas in the F344 rat: morphological and functional changes. Exp. Gerontol. 42, 629-638; Bielefeld, E.C., Coling, D., Chen, G.D., Li, M.N., Tanaka, C., Hu, B.H., Henderson, D., 2008. Age-related hearing loss in the Fischer 344/NHsd rat substrain. Hear. Res. 241, 26-33], aged Fischer 344 (F344) rats with severe hearing loss retain many outer hair cells (OHCs) especially in the middle turn of the cochlea. The current study confirmed the previous findings showing that aged OHCs were present, but dysfunctional. Distortion product otoacoustic emissions (DPOAE), which are believed to reflect in vivo OHC motility, were absent in the aged rats while the majority of OHCs (>80%) were present and morphologically intact. There was no detectable injury of OHC stereocilia as assessed by actin-staining and examination under the light microscope. Cochlear microphonics (CM) at 12kHz, recorded from the middle turn, only showed a slight age-related reduction, indicating a normal mechanoelectrical transduction apparatus in the remaining OHCs in the cochlear regions with 10-20% OHC loss. Activities of succinate dehydrogenase (SDH), an enzyme shared by the citric acid cycle and the mitochondrial electron transport chain (METC), were also at normal levels in aged OHCs. Importantly, aged OHCs showed reduced levels of prestin immunolabeling compared to young controls. Together with our previous finding showing that the stria vascularis and endocochlear potential were essentially normal in aged F344 rats [Bielefeld, E.C., Coling, D., Chen, G.D., Li, M.N., Tanaka, C., Hu, B.H., Henderson, D., 2008. Age-related hearing loss in the Fischer 344/NHsd rat substrain. Hear. Res. 241, 26-33], the results suggest that disruption of prestin is the major cause of DPOAE loss and loss of cochlear sensitivity.

Apoptotic cell death has been implicated in cochlear degeneration during aging. To better understand the impact and the biological process of outer hair cell (OHC) apoptosis, we investigated the contribution of apoptotic cell death to the formation of the OHC lesions, and observed the temporal patterns of the occurrence of apoptotic events associated with the mitochondrial pathway in Fischer 344/NHsd rats, with ages ranging from 20 to 27 months. The results showed that the ratio of apoptotic to necrotic OHCs was 8:1. During the process of cell degeneration, the onset of Bax expression, cytochrome c release, and nuclear DNA fragmentation preceded the onset of nuclear condensation. In contrast, the activation of caspases-3 and -9, as well as the degradation of F-actin, took place after the onset of nuclear condensation. The results of this study suggest that the initiation of nuclear degradation is a caspase-3-independent process. Moreover, the study revealed that OHCs with Bax expression or cytochrome c release could enter either the apoptotic or necrotic pathway, suggesting the presence of a regulatory mechanism that guides degenerating OHCs to die via either the apoptotic or necrotic pathway.

The relationship between outer hair cell (OHC) loss and cochlear sensitivity is still unclear, because in many animal models there exist surviving but dysfunctional OHCs and also injured/dead inner hair cells (IHC). Styrene is an ototoxic agent, which targets and destroys OHCs starting from the third row to the second and first rows depending on the exposure level. The remaining cells may be less affected. In this experiment, rats were exposed to styrene by gavage at different doses (200-800 mg/kg/day) for varying periods (5 days/week for 3-12 weeks). An interesting finding was that the cochlear sensitivity was not affected in a few rats with all OHCs in the third row being destroyed by styrene. A further loss of OHCs was usually accompanied with a linear input/output (I/O) function of cochlear compound action potentials (CAP), indicating the loss of cochlear amplification. However, normal CAP amplitudes at the highest stimulation level of 90 dB SPL were often observed when all OHCs were destroyed, indicating normal function of the remaining IHCs. The OHC-loss/hearing-loss relation appeared to be a sigmoid-type function. Initially, styrene-induced OHC losses (<33%) did not result in a significant threshold shift. Then CAP threshold shift increased dramatically with OHC loss from 33% to 66%. Then, CAP threshold changed less with OHC loss. The data suggest a tri-modal relationship between OHC loss and cochlear amplification. That is, under the condition that all surviving OHCs are ideally functioning, the cochlear amplifier is not affected until 33% of OHCs are absent, then the gain of the amplifier decreases proportionally with the OHC loss, and at last the amplifier may fail completely when more than 67% of OHCs are lost.

Studies of the F344 rat have shown a variety of age-related auditory anatomy and physiology changes. The current study was undertaken to clarify the ARHL in the F344 rat, by examining the auditory pathway of the F344/NHsd substrain that is distributed by Harlan Laboratories for research in the United States. The F344/NHsd rat begins to lose its hearing at about 12 months, and by 24 months, there are 50-60 dB auditory brainstem response threshold shifts at 20 and 40 kHz and 20 dB losses at 5-10 kHz. Distortion product otoacoustic emissions (DPOAE) amplitudes at 1.8-12 kHz stimuli were depressed in the older (18-24 months) rats. Amplitude input-output functions of the compound action potential (CAP) were also depressed across frequency. The endocochlear potential (EP) was 90-100 mV in the 3 month old rats. All but one of the 24 month old rats' EPs were in the +75-85 mV range. Tympanometry revealed no differences in middle ear function between the young and older rats. Collectively, these findings suggest damage to the outer hair cells, but anatomical examination of the outer hair cells revealed a relative lack of cell loss compared to the magnitude of the hearing and DPOAE loss.

Outer hair cells (OHCs) play an important role in cochlear amplification via their length changes (electromotility). A noise-induced cochlear amplification loss leading to a permanent threshold shift (PTS) was observed without a significant hair cell loss in rats [Chen, G.D., Liu, Y., 2005. Mechanisms of noise-induced hearing loss potentiation by hypoxia. Hear. Res. 200, 1-9.]. Since motor proteins are inserted in the OHC lateral membrane, any change in the OHC plasma membrane may result in a loss of OHC electromotility, leading to a loss of cochlear amplification. In this study, the lateral diffusion in the OHC plasma membrane was determined in vitro in guinea pigs by fluorescent recovery after photobleaching (FRAP) after an in vivo noise exposure. The lateral diffusion in the OHC plasma membrane demonstrated a length-dependence, which increased as OHC length increased. A reduction in the lateral diffusion was observed in those OHCs with lengths of 50-70 microm after exposure to an 8-kHz octave band noise at 110 dB SPL for 3h. This membrane fluidity change was associated with the selective PTS at frequencies around 8 kHz. The reduction of the lateral diffusion in the OHC lateral wall indicated that noise could impair the micromechanics of the OHC lateral wall and might consequently impair OHC electromotility to induce threshold shift.

Noise-induced permanent loss of cochlear amplification was observed previously with the majority of outer hair cells (OHCs) still surviving in the cochlea and even with a normal OHC receptor potential, indicated by CM (cochlear microphonics) recording [Chen, G.D., Fechter, L.D., 2003. The relationship between noise-induced hearing loss and hair cell loss in rats. Hear. Res. 177(1-2), 81-90; Chen, G.D., Liu, Y., 2005. Mechanisms of noise-induced hearing loss potentiation by hypoxia. Hear. Res. 200, 1-9]. This study focused on effects of an intense noise exposure (10-20 kHz at a level of 110 dB SPL for 4 h) on the OHC motor protein (prestin) and structural proteins in the OHC membrane skeleton. The noise exposure significantly disrupted CM and CAP (cochlear compound action potential). The injured CM recovered after 1-week resting period. The impaired CAP at frequencies lower than the noise band also recovered. However, the CAP recovery at frequencies of the noise band stopped at a linear line one week after the noise exposure, indicating a permanent loss of cochlear amplification. Gene expression of prestin, beta-spectrin, and beta-actin was significantly up-regulated after the noise exposure. The elevated gene expression peaked at the 3rd post-exposure day and returned to baseline 4 weeks after the noise exposure. The up-regulated gene expression may be in response to injury of the proteins, which may be responsible for the loss of cochlear amplification.

Potentiation of noise-induced permanent threshold shift (PTS) by hypoxia has been reported [Hear. Res. 172 (1-2) (2002) 186]. In this study in rats, effects of noise (110 dB SPL), hypoxia (10% O(2)), and their combination have been determined on different cochlear potentials and on the expression of genes coding proteins in the outer hair cell (OHC) membrane skeleton (beta-actin) and in the mitochondrial respiratory chain (SDHa & b). The noise exposure alone caused CAP threshold shift only in the noise-band. The combined exposure to noise and hypoxia caused an about 40-dB PTS at all frequencies within and above the noise band. Loss of the cochlear amplification was not always related to the CM-suppression. SP was only affected at high frequencies by the combined exposure. Gene expression of beta-actin was up-regulated by the noise exposure, which was blocked by hypoxia. Gene expression of SDHa was also up-regulated by the noise and the combined exposure. The data suggest that loss of the cochlear active process, due to damage to the OHC membrane skeleton and to the cellular energy generation system, is related to the noise-induced hearing loss potentiation by hypoxia. Inner hair cell damage may also be involved in the hypoxia potentiation in the basal turn.

Noise-induced hearing loss (NIHL) and hair cell loss are known to show only a moderate correlation. One reason for this is that NIHL may reflect not only the sum of dead hair cells, but also the sum of impaired but still living hair cells. This report compares hair cell loss in different cochlear regions in rats with noise-induced compound action potential (CAP) threshold elevation at corresponding frequencies. CAP threshold elevation and hair cell loss were determined 4 weeks after noise exposure. In the apical turn (<35% from the apex) there was no hair cell loss even when a 60 dB CAP threshold elevation was induced. In the region of 40-60% from the apex in the middle turn, significant hair cell loss was not observed until CAP threshold elevation exceeded about 40-50 dB. This critical level decreased towards the basal turn. In the basal turn, outer hair cell (OHC) loss was observed in almost all of the noise-exposed rats, even in some cases without detectable NIHL, but inner hair cell (IHC) loss was still not observed until 50 dB threshold elevation. In the region of 75-90% from the apex related to the highest frequencies tested in this study (30-40 kHz), a linear NIHL/OHC loss relationship was observed. The results of this paper suggest that the high frequency hair cells in rat cochlea may die relatively rapidly after injury, leading to a linear relation between NIHL and hair cell loss, but that the low frequency hair cells may survive without auditory function.

Chemical asphyxiants have been shown to potentiate noise-induced hearing loss (NIHL) in our previous reports. However, it is still unclear whether hypoxia interacts with noise to potentiate NIHL. This is an important issue, since many people at risk of exposure to noise may also suffer from hypoxia. In the present study, rats were exposed to 14.1-kHz octave-band noise at 105, 110, and 115 dB SPL and hypoxic air (10% O(2) and 18% O(2)) for 4 h. Cochlear compound action potential threshold loss and hair cell loss were determined 4 weeks after the exposure. Though the hypoxia did not cause hearing loss and hair cell loss, the combined exposure to noise and hypoxic air caused more hearing loss and hair cell loss than the noise alone. The NIHL potentiation by hypoxia appeared to increase linearly with the hypoxia level. 10% O(2) exposure significantly potentiated NIHL and 18% O(2) exposure also showed an evident NIHL potentiation. This suggests that people suffering from hypoxia may have increased risk to noise trauma.

While a clear role has been proposed for glutamate as a putative neurotransmitter at the inner hair cell type I spiral ganglion cell synapse, the possible role of excessive glutamate release in cochlear impairment and of NMDA receptors in such a process is uncertain. The present study compares the protective effects of (+)-MK-801, an NMDA receptor antagonist, and the relatively inactive isomer (-)-MK-801 against permanent noise-induced hearing loss (NIHL). The study also asks whether (+)-MK-801 can protect against the NIHL potentiation by carbon monoxide (CO). Rats (n = 6) were exposed to 100-dB, 13.6-kHz octave-band noise for 2 h after receiving injection of (+)-MK-801 hydrogen maleate (1 mg/kg), (-)-MK-801 hydrogen maleate (1 mg/kg), or saline. Other groups of animals were exposed to the combination of noise and CO (1200 ppm) after receiving (+)-MK-801 or saline. Additional subjects received (+)-MK-801, saline or CO exposure alone. Compound action potential (CAP) threshold sensitivities were compared 4 weeks after the exposures. The results show significant protection by (+)-MK-801 against the permanent CAP threshold elevation induced by noise alone, but no protective effect of (-)-MK-801. (+)-MK-801 produced limited protection against threshold shifts induced by the combination of noise and CO. Outer hair cell (OHC) loss was not protected by (+)-MK-801 administration. The data suggest that NMDA receptor stimulation may play a role in NIHL resulting from fairly mild noise exposure. The data do not support a role for NMDA receptor stimulation in the potentiation of NIHL that results from simultaneous exposure to CO and noise.

Hair cell loss is often used as a histological correlate of hearing loss. However, the histological and the physiological data are not always well correlated. This paper investigates the use of succinate dehydrogenase (SDH) activity in the hair cells as a marker of cellular dysfunction and so the loss of auditory sensitivity. In our previous studies, potentiation of noise-induced auditory threshold elevation by carbon monoxide (CO) was observed [Chen and Fechter, 1999; Chen et al., 1999]. However, its histological basis is still unclear. In this study, rats were exposed to 100-dB octave-band noise (center frequency=13.6 kHz, 2 h) or to the combination of the noise and CO (1200 ppm). Threshold elevation of compound action potential (CAP) and cochlear histological changes were assessed 4 weeks after exposure. The noise alone caused CAP threshold elevations with little if any or without hair cell loss. However, the SDH activity in the hair cells decreased after the exposure. The SDH reduction, especially in the inner hair cells, was well related to the loss of auditory sensitivity. The combined exposure to noise and CO caused more severe CAP threshold elevation and SDH activity reduction than did the noise alone and it also caused significant outer hair cell loss. However, across all the test frequencies, neither the hair cell loss nor the SDH reduction alone had good correlation to the reduction of the auditory sensitivity. Under this situation, CAP threshold elevation seemed to follow OHC loss at high frequencies and to follow SDH reductions in the IHCs at low frequencies, where no hair cell loss occurred.

Intermittent noise causes less hearing loss than continuous noise of equal intensity. The reduction in damage observed with intermittent noise may be explained by the fact that the auditory system has time to recover between the noise phases. Simultaneous carbon monoxide (CO) exposure produces greater noise-induced hearing loss than does noise alone (Chen and Fechter, 1999). In the present study, intermittent noise (octave-band with a center frequency of 13.6 kHz, 100 dB) of a 2 h total duration but with a different duty cycle (% of noise during exposure) was used. The intermittent exposure that had a shorter noise duty cycle induced a less permanent threshold shift (PTS) than those that had a longer noise duty cycle (or less rest periods). This relation between the loss in compound action potential (CAP) sensitivity and the noise duty cycle (or rest period) was abolished by the presence of CO. The cochlear microphonic (CM) amplitude revealed similar results to those seen using the CAP. While intermittent noise that had a short noise duty cycle did not cause hair cell loss by itself, the combined exposure to noise and CO (1200 ppm) caused remarkable OHC loss in the basal turn.

The responses of 100 inferior colliculus neurons to syllables differing in voice onset time (VOT) presented binaurally were studied. As in a previous study of monaural responses (Chen et al., 1996), the responses consisted of 1-3 response 'components', referred to as release responses, VOT responses or vowel responses. The discharge rate of all response components could vary cyclically with the interaural time difference (ITD). The maximal rate often occurred at an ITD around +0.2 ms (contralateral ear leading). Response frequencies (RF) based on the periodicity of the delay curves varied with the characteristic frequency (CF) and VOT. RF also varied across response components. Overall, RF was correlated with the 'most effective frequency', the spectral component with the highest amplitude, relative to the tuning curve. VOT response latency for a given syllable could change by a few ms with ITD, but those changes were small, relative to the range of latencies observed over the entire range of VOTs. Changes in ITD produced large changes in the overall shape of the peristimulus time histogram. There was no relation between the histogram shape and perceptual consonant categories.

In previous studies from our lab, broadband noise induced hearing loss has been found to be potentiated by simultaneous carbon monoxide (CO) exposure. In the present study, octave-band noise induced auditory impairment was studied with the presence of CO at levels of 1500, 1200, 700, 500 and 300 ppm and zero (noise alone). Four octave-band noises (1.2-2.4, 2.4-4.8, 4.8-9.6 and 9.6-19.2 kHz) were used. Experimental subjects (rats) were grouped for the exposure (8 h) to each noise, CO and their combinations. The compound action potential (CAP) and cochlear microphonics (CM) were recorded 4 weeks after the exposure. The noise induced elevation of the CAP threshold and the CM iso-amplitude curve were potentiated by the simultaneous CO exposure when the CO level reached 500 ppm or higher. CO exposure alone had no effect on CAP or CM. The CO potentiation can occur in any frequency region depending on the noise band. The combined exposure can also induce threshold shifts in some cases in which both the noise and the CO alone did not cause threshold shifts. The size of the potentiation shown by CAP and CM was similar, indicating a possible origin of the CO potentiation from the damage to the outer hair cells. Interestingly, the hearing loss induced by noise alone gradually recovered (partially), but the hearing loss caused by the combined exposure did not. The potentiation may be due to the reduction of the cell's ability to repair noise induced damage by CO.

The responses of 274 inferior colliculus (IC) central nucleus neurons from 20 chinchillas were studied. Characteristic frequency (CF) increased as the IC was traversed in the dorsal-ventral direction. Most units had little or no spontaneous activity, with a mean threshold for response of about 30 dB SPL across all units. Tuning curve width varied between units, with a significant increase in Q20, with increasing CF. Peri-stimulus time histogram (PSTH) types were similar to those reported for cat inferior colliculus units. Transient, sustained, pauser, and buildup types were observed, with transient responses predominating. Response area (RA) types were also similar to those of cat IC units, with most units displaying stable best frequencies across a range of stimulus intensity levels. For a few units, excitatory RA regions were surrounded by inhibitory sidebands. Nonmonotonic discharge rate vs. stimulus intensity level functions were common in all CF ranges and for all PSTH and RA types. Mean first spike latencies, however, differed across PSTH groups, owing to the temporal definitions of these PSTH shapes. Latencies of sustained units were significantly longer than those of transient units, and buildup PSTHs showed significantly longer latencies than any other group.

The effects of the stimulus duration (10 to 300 ms) on the responses of chinchilla inferior colliculus neurons to pure tones were studied in 41 units. The responses of the majority of the neurons (90%) were classified as sustained, onset, pause with onset peak and pause without onset peak response patterns. Three neurons were found to have response to the stimulus offset (offset response pattern). One neuron responded to the sound with the decrease of the spontaneous discharge rate (inhibitory response pattern). The responses restricted within the stimulus duration could be simply predicted from the peristimulus time histogram (PSTH) to the longer duration. The leading part of the PSTH to the longer stimulus duration resembled that to the shorter stimulus duration. The function of the spike number versus duration was correlated with the PSTH patterns. The response following the stimulus offset (including inhibitory response) could vary with the stimulus duration nonmonotonically and show a band-pass or band-reject property. Overall, four (about 10%) of the neurons could be regarded as duration-tuned units. The duration selectivity could be understood by the interaction between the ongoing and the offset process of the neurons.

The evaluation of the spontaneous activity of 471 units from the external nucleus of the IC revealed that salicylate induces an increase of the spontaneous activity and the emergence of a bursting type of activity longer than 4 spikes. For sharply tuned units, the affected cells were from the frequency range of 10-16 kHz, which corresponds to the behaviorally measured pitch of salicylate-induced tinnitus in rats. An exogenous calcium supplement, provided under the conditions shown to attenuate the behavioral manifestation of salicylate-induced tinnitus, abolished the modification of the spontaneous activity induced by salicylate. Finally, profound changes of activity were observed for cells not responding to contralateral sound. We propose that the observed long bursts of discharges represent tinnitus-related neuronal activity. The results are consistent with the hypothesis that GABA-mediated disinhibition is involved in the processing of tinnitus-related neuronal activity.